Over the past three decades a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen remarkable growth is the cephalosporins. A majority of the cephalosporins are administered using suspension compositions. However, bitter taste and bioequivalence are major drawbacks of some cephalosporins such as cefuroxime axetil and cefpodoxime proxetil.
U.S. Pat. No. 4,562,181 discloses that cefuroxime axetil can be produced in relatively impure amorphous form or in the form of purer crystalline material. This patent further reveals that substantially pure, crystalline cefuroxime axetil does not have the best balance of properties for commercial use. As per this patent, Cefuroxime axetil is advantageously used in a highly pure, substantially amorphous form. Highly pure cefuroxime axetil when in substantially amorphous form has higher bioavailability upon oral administration than when in crystalline form.
U.S. Pat. No. 4,865,851 discloses that Cefuroxime axetil, both in crystalline form and the amorphous form, has a tendency to form a gelatinous mass when contacted with aqueous media. This gelling effect is temperature dependent but does occur at temperatures of about 37° C., i.e. at the physiological temperatures at which the disintegration of an orally-administered granule would take place. Where there is a relatively slow dispersion of cefuroxime axetil into the surrounding aqueous medium following ingestion, there is the risk that cefuroxime axetil present in the composition may gel. Such gel formation would lead to poor dissolution of the cefuroxime axetil and hence poor absorption from the gastrointestinal tract, i.e. low bioavailability. In the case of granule formulations the use of particles of small diameter and high surface area is desirable to avoid such gelling.
U.S. Pat. No. 4,865,851 also discloses that cefuroxime axetil has an extremely bitter taste which is long lasting and which cannot be adequately masked by the addition of sweeteners and flavors to conventional granule presentations. Cefpodoxime proxetil is a highly hydrophobic, bitter drug that has a tendency to form a gel in aqueous media, which thereby results in slow dissolution and hence poor bioavailability. It is therefore necessary that the pharmaceutical composition be formulated such that bridging of molecules to form a gel is prevented and thereby, the dissolution is improved.
Various investigators have tried different means of overcoming these difficulties.
U.S. Pat. No. 4,865,851 disclose integral lipid coatings as a means of overcoming the extremely bitter taste of cefuroxime axetil and the gelling tendency of Cefuroxime Axetil. However, the process of lipid coating involves the use of specialized equipment such as spray drying apparatus, process criticality and may lead to degradation of the active principle if the proper lipid mixture is not selected. In addition, lipid coating results in extreme variability in the bioavailability of the drug from the suspension formulation.
U.S. Pat. No. 6,346,530 B1 and U.S. Pat. No. 6,323,193 B1 disclose a mixture of amorphous cefuroxime axetil with crystalline cefuroxime axetil such that crystalline cefuroxime axetil forms from about 7 to about 25 weight percent and about 12 to about 25 weight percent respectively of the total amount of amorphous cefuroxime axetil together with crystalline cefuroxime axetil to achieve a comparable bioavailability profile as pure amorphous cefuroxime axetil. These patents disclose the surprising result that it is possible to achieve bioequivalence between formulations comprising of pure amorphous cefuroxime axetil and formulations comprising of up to 25% crystalline cefuroxime axetil.
It would be desirable to have a stable taste masked dosage form, which will address these issues while making use of the less expensive, conventional techniques of making pharmaceutical formulations.
It is now surprisingly found that when cephalosporins are formulated as discrete dosage units such as pellets, the resulting formulations are stable and taste masked.
The present invention is surprising in that such a formulation might be expected to have stability issues due to the stressful processes of preparation and/or bioequivalence issues due to the coating procedures. However, the pharmaceutical compositions of the present invention are not only adequately taste masked but also show satisfactory stability and bioequivalence.
The present inventors have also surprisingly found that contrary to the disclosures in U.S. Pat. No. 4,562,181 and Ranbaxy's patents U.S. Pat. No. 6,346,530 B1 and U.S. Pat. No. 6,323,193 B1, it is possible to make a bioequivalent formulation comprising of substantial quantities of crystalline cefuroxime axetil when the particle size of the crystalline cefuroxime axetil is reduced such that 100% of the particles have a particle size below 250μ.